Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them

ABSTRACT

The invention concerns novel substituted 6-benzyl-4-oxopyrimnidines of general formula (A). These compounds inhibit reverse transcriptase encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof, and find their application in the prevention and treatment of HIV infection and the treatment of the resulting acquired immune deficiency syndrome (AIDS). Pharmaceutical compositions containing the compounds and a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV are also envisaged.

[0001] The present invention is concerned with compounds which inhibitthe reverse transcriptase encoded by human immunodeficiency virus (HIV)or pharmaceutically acceptable salts thereof and are of value in theprevention of infection by HIV, the treatment of infection by HIV andthe treatment of the resulting acquired immune deficiency syndrome(AIDS). It also relates to pharmaceutical compositions containing thecompounds and to a method of use of the present compounds and otheragents for the treatment of AIDS arid viral infection by HIV.

BACKGROUND OF THE INVENTION

[0002] A retrovirus designated human immunodeficiency virus (HIV) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.

[0003] Currently available drugs for AIDS therapy are divided into twogroups: those that prevent infection of target cells [nucleoside (NRTIs)and non-nucleoside reverse transcriptase inhibitors (NNRTIs)], and thosethat prevent HIV-1-infected cells from yielding infectious viruses(protease inhibitors). Monotherapy with antiretroviral agents has shownlimited effects, very likely due to the interplay of phenomena such as:high viral loads and multiplication rates of HIV, incomplete inhibitionof viral replication and emergence of drug resistant mutants. For thisreason, combination therapies with two or more drugs have been proposedfor a more effective treatment of AIDS. Potent suppression of HIVreplication over prolonged periods has been accomplished with regimensincluding reverse transcriptase and protease inhibitors, although onstopping therapies viraemia has rapidly reappeared. In the attempt toobtain better results, research is now focused on exploiting new targetsand enhancing the activity of “old” drugs. Among the latter, NNRTspossibly endowed with better pharmacokinetic profiles, capability toinhibit clinically relevant mutants and, hopefully, to minimize HIVmultiplication are being pursued.

[0004] Compounds of the present invention aredihydro-alkyloxy-benzyl-oxopyrimidines (DABOs) which potently inhibitHIV multiplication targeting reverse transcriptase withoutbioactivation.

BRIEF DESCRIPTION OF THE INVENTION

[0005] Novel compounds of formula A:

[0006] as herein defined, are disclosed. These compounds are useful inthe inhibition of HIV reverse transcriptase, the prevention of infectionby HIV, the treatment of infection by HIV and in the treatment of AIDS,either as compounds, pharmaceutically acceptable salts (whenappropriate), pharmaceutical composition ingredients, whether or not incombination with other antivirals, anti-infectives, immunomodulators,antibiotics or vaccines. Methods of treating AIDS, methods of preventinginfection by HIV, and methods of treating infection by HIV are alsodisclosed.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

[0007] This invention is concerned with the compounds of formula Adescribed below, combinations thereof, or pharmaceutically acceptablesalts thereof, in the inhibition of HIV reverse transcriptase, theprevention or treatment of infection by HIV and in the treatment of theresulting acquired immune deficiency syndrome (AIDS). The compounds ofthis invention include those with structural formula A:

[0008] wherein:

[0009] X is —O, —CH₂, —CHK (wherein K is —H, —C₁₋₄, alkyl,—C₃₋₆Cycloalkyl), —S, —NK (wherein K is —H, —Cl₁₋₄alkyl,—C₃₋₆cycloalkyl), -aryl, -arylalkyl;

[0010] R is —H, —C₁₋₄alkyl (containing one or more of heteroatoms likeO, S, N), —C₃₋₆cycloalkyl (containing one or more of heteroatoms like O,S, N), -aryl, -arylakl, heterocycle;

[0011] Y is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl;

[0012] Z is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl;

[0013] R₁ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃,-aryl), —SW (wherein W is —H, —CH₃, -aryl);

[0014] R₂ is —H, —C₁₋₄alkyl, -halogen, —NO₂, (wherein W is —H, —CH₃,-aryl); —SW (wherein W is —H, —CH₃, -aryl);

[0015] R₃ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃,-aryl); —SW (wherein W is —H, —CH₃, -aryl)

[0016] R₄ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃,-aryl); —SW (wherein W is —H, —CH₃, -aryl)

[0017] R₅ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃,-aryl), —SW (wherein W is —H, —CH3, -aryl);

[0018] pharmaceutically acceptable salts or soluble derivatives thereof;

[0019] preparation process of derivatives thereof;

[0020] a method of preventing infection of HIV, or of treating infectionby HIV or of treating AIDS, comprising administering to a mammal aneffective amount of compounds claimed;

[0021] a pharmaceutical composition useful for inhibiting HIV reversetranscriptase, comprising an effective amount of compounds claimed, anda pharmaceutically acceptable carrier;

[0022] a pharmaceutical composition useful for preventing or treatinginfection of HIV or for treating AIDS, comprising an effective amount ofcompounds claimed, and a pharmaceutically acceptable carrier.

[0023] The most preferred compounds of this invention are those of table1.

[0024] The compounds of the present invention may have asymmetriccenters and occur as racemates, racemic mixtures, individualdiastereomers, or enantiomers, with all isomeric forms being included inthe present invention.

[0025] When any variable occurs more than one time in any constituent orin formula A of this invention, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

[0026] As used herein except where noted, “alkyl” is intended to includeboth branched- and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; “Halogen” or “Hal” as usedherein, means fluoro, chloro, bromo and iodo.

[0027] As used herein, with exceptions as noted, “aryl” is intended tomean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7members in each ring, wherein at least one ring is aromatic. Examples ofsuch aryl elements include phenyl, naphthyl, tetrahydronaphthyl,biphenyl.

[0028] The term heterocycle or heterocyclic, as used herein except wherenoted represents a stable 5- to 7-membered monocyclic or stable 8- to11-membered bicyclic heterocyclic ring which is either saturated orunsaturated, and which consists of carbon atoms and from one to threeheteroatoms selected from the group consisting of N, O and S; andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure.

[0029] The pharmaceutically-acceptable salts of the novel compounds ofthis invention that are capable of salt formation (in the form of water-or oil-soluble or dispersible products) include the conventionalnon-toxic salts or the quaternary ammonium salts of these compounds,which are formed, e.g.; from inorganic or organic acids or bases.

[0030] In preferred embodiments, a compound of the present invention isadministered in combination or alternation with AZT, D4T, FTC(2′,3′-dideoxy-3′-thia-5-fluorocytidine); 3TC (Epivir, Glaxo Wellcome,Inc.), AZDU (3′-Azido-2′,3′-dideoxyuridine); 141W94 (amprenavir.GlaxoWellcome, Inc.); Viramune (nevirapine), Rescriptor (delavirdine);or DMP-266 (efavirenz). Other examples of antiviral agents that can beused in combination or alternation with the compounds disclosed hereinfor HIV therapy include DDI, DDC, Delaviridine, β-LddA,β-L-3′-azido-d5FC, carbovir, acyclovir, interferon, stavudine, CS-92(3′-azido-2′,3′-dideoxy-5-methyl-cytidine), 3′-azido nucleosides, andβ-D-dioxolane nucleosides such as β-D-dioxolanylguanine (DXG),β-D-dioxolanyl-2,6-diaminopurine (DAPD), andβ-D-dioxolanyl-6-chloropurine (ACP).

[0031] Preferred protease inhibitors include indinavir({1(1,S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erythro-pentoamidesulfate; Merck), nelfinavir (Agouron), ritonavir (Abbot), and saquinavir(Invirase; Roche).

[0032] Nonlimiting examples of other compounds that can be administeredin combination or alternation with the compounds of the presentinvention to augment the properties of the drug on administrationinclude abacavir:(1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanolsuccinate (1592U89, a carbovir analog; Glaxo Wellcome); zidovudine: AZT,3′-azido-3′-deoxythymidine (Glaxo Wellcome); BILA 1906:N-{1S-[[[3[2S-{(1,1-dimethylethylamino]carbonyl}-4R-]3-pyridinylmethyl)thio]-1-piperidinyl]-2-R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl}-2-quinolinecarboxamide(Bio Mega/Boehringer-Ingelheim); BILA 2185:N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethylphenoxy)-1-oxoethyl]amino]-2R-hydroxy-4-phenylbutyl]4R-pyridinylthio)-2-piperidinecarboxamide(Bio Mega/Boehringer-Ingelheim); BM+51.0836:triazoloisoindolinonederivative; BMS 186,318: aminodiol derivative HIV-1 protease inhibitor(Bristol-Myers-Squibb); d4API:9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanel]adenine (Gilead);stavudine: d4T, 2′,3′-didehydro-3′-deoxythymidine (Bristol-MyersSquibb);efavirenz: DMP-266, a 1,4-dihydro-2H-3, 1-benzoxazin-2-one; HBY097:S-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione;HEPT: 1-[(2-hydroxyethoxy)methyl]6-(phenylthio)thymine; KNI-272:(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid-containing tripeptide;L-697,593; 5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2-(1H)-one;L-735,524: hydroxy-aminopentane amide HIV-1 protease inhibitor (Merck);L-697,661:3-{[(-4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2-(1H)-one;L-FDDC: (−)-β-L-5-fluoro-2′,3′-dideoxycytidine; L-FDOC:(−)-p-L-5-fluoro-dioxolane cytosine;6-benzyl-1-ethoxymethyl-5-isopropyluracil (1-EBU; Triangle/Mitsubishi);nevirapine:11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridol[3,2-b:2′,3′-e]diazepin-6-one(Boehringer-Ingelheim); PFA: phosphonoformate (foscarnet; Astra); PMEA:9-(2-phosphonylmethoxyethyl) adenine (Gilead); PMPA:(R)-9-(2-phosphonyl-methoxypropyl)adenine (Gilead); Ro 31-8959:hydroxythethylamine derivative HIV-1 protease inhibitor (Roche);RPI-3121: peptidyl protease inhibitor,1-[(3s)-3-(n-alpha-benzyloxycarbonyl)-1-asparginyl)-amino-2-hydroxy-4-phenylbutyryl]-n-tert-butyl-1-prolineamide; 2720:6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4-dihydro-quinoxalin-2-(1H)thione;SC-52151: hydroxyethylurea isostere protease inhibitor (Searle);SC-55389A: hydroxyethyl-urea isostere protease inhibitor (Searle); TIBOR82150:(+)-(SS)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]-benzodiazepin-2-(1H)-thione(Janssen); TIBO 82913:(+)-(5S)4,5,6,7,-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1jk][1,4]benzodiazepin-2-(1H)-thione(Janssen);TSAO-m3T:[2′,5′-bis-O-(tertbutyldimethylsilyl)3′-spiro-5′-(4′-amino-1′,2′-oxathiole-2′,2′-dioxide)]-β-D-pentofuranosyl-N3-methylthymine;U90152:1-[3-[(1-methylethyl)-amino]2-pyridinyl]4-[[5[(methylsulphonyl)-amino]-1H-indol-2-yl]carbonyl]piperazine;UC: thiocarboxanilide derivatives (Uniroyal);UC-781=N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide;UC-82=N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-thiophenecarbothioamide;VB 11,328: hydroxyethylsulphonamide protease inhibitor (Vertex); VX478:amprenavir, 141W94, hydroxyethylsulphonamide protease inhibitor(Vertex/Glaxo Wellcome); XM 323: cyclic urea protease inhibitor (DupontMerck), delaviridine (Pharmacia Upjohn), famciclovir, gancyclovir, andpenciclovir. In another embodiment, a compound of the present inventionis administered in combination with LG1350, which has the followingstructure.

[0033] Anhydrous pyridine (400 mmoles, 32.5 ml) was added with stirringunder nitrogen atmosphere into an ice-cooled solution of2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrurm's acid) (165 mmoles, 23.75g) in anhydrous dichloromethane (50 ml). The resulting solution wastreated, over a 2 h period at 0° C. under nitrogen atmosphere, with asolution of crude arylacetyl chloride in anhydrous dichloromethane (50ml). Arylacetyl chloride was prepared before use by refluxing the properarylacetic acid (43.2 mmoles) with thionyl chloride (21.3 ml) undernitrogen atmosphere for 2 h. Then, the mixture was stirred for 2 h atroom temperature, poured into crushed ice and treated with 2N HCl (100ml). The organic layer was separated and the aqueous solution wasextracted twice with dichloromethane (25 ml). The organic phase and theextracts were combined, washed with brine, dried and evaporated. Thesolid residue was dissolved in anhydrous methanol (250 ml) and thesolution was refluxed for 20 h. After cooling, metal sodium (0.16g-atoms, 3.68 g) was carefully added and the mixture was stirred untildissolution was complete. Alkyl halide (160 mmoles) was dropped into thesolution and the resulting mixture was heated at reflux for 4-12 h.After cooling, the solvent was removed and the residue treated withwater (200 ml) and extracted with chloroform (3×100 ml). The organiclayer was washed with brine (2×100 ml), dried and evaporated to give thedesired compound, which was purified by passing through a silica gelcolumn (chloroform as eluent).

[0034] In the above reaction, arylacetic acid (Scheme “A”) or arylacetylchloride can be replaced with the corresponding 1-arylacetylimidazolide(Scheme “B”) or with arylacetylethoxycarbonylanhydride, whereas theMeldrum's acid can be replaced with ethyl acetylacetate, ethylalkylmalonate or ethyl alkylmalonate potassium salt, to give the properethyl arylacetylalkylacetates in high yields.

[0035] Preparation of Compounds (I) with X═O (Scheme A).

[0036] The proper methyl arylacetylalkylacetate (10 mmoles) in methanol(50 ml) was added to a well-stirred suspension of O-methylisoureahydrogen sulphate (15 mmoles, 2.58 g) and calcium hydroxide (16 mmoles,1.18 g) in water (50 ml). The resulting mixture was stirred at roomtemperature for 72 h, then concentrated, made acid (pH 5) with 0.5Nacetic acid and extracted with ethyl acetate (3×50 ml). The combinedorganic extracts were washed with brine (100 ml), dried and evaporatedto dryness. The residue was purified by crystallization from the propersolvent yielding pure5-alkyl-6-benzyl-3,4-dihydro-2-methoxypyrimidin-4-one. This compound wasthen refluxed with the proper potassium alkoxide (100 mmoles ofpotassium metal in 20-30 ml of alcohol freshly distilled on sodiummetal) under nitrogen atmosphere until starting material disappeared atthe TLC control. After cooling, the mixture was concentrated, made acid(pH 5) with 0.5N acetic acid and extracted with ethyl acetate (3×50 ml).The combined extracts were washed once with brine (100 ml), dried andevaporated to give the required2-alkoxy-5-alkyl-6-benzyl-3,4-dihydropyrimidin-4-one derivative, whichwas recrystallized from a suitable solvent or purified by columnchromatography (silica gel; ethyl acetate:chloroform 1:1). Physical andchemical data of representative compounds of the invention are reportedin table 1; cytotoxicity and anti-HIV-1 activity data are reported intable 2.

[0037] The proper ethyl arylacetylalkylacetate (31.5 mmoles) wassuccessively added to a stirred solution of sodium metal (0.063 g-atoms)in 50 mL of absolute ethanol (50 ml) thiourea (43 mmoles). The mixturewas heated while stirring at reflux for 5 h. After cooling, the solventwas distilled in vacuo at 40-50° C. until dryness and the residue wasdissolved in water (200 mL) and made acid (pH 5) with 0.5N acetic acid.The resulting precipitate (the crude 2-thiouracil derivative) wasfiltered under reduced pressure, washed with diethyl ether, vacuum driedat 80° C. for 12 h and then crystallized from the proper solvent.

[0038] Then, according to method A, iodomethane (8 mmoles, 1.13 g) wasadded to a suspension containing the proper 2-thiouracil derivative (4mmoles) in anhydrous N,N-dimethylformamide (2 ml), and the resultingmixture was stirred at room temperature until the starting materialdisappeared at the TLC control (silica gel; n-hexane: ethyl acetate:methanol 12:3:1). Then the reaction content was poured on cold water(100 mL) and extracted with ethyl acetate (3×50 ml). The organic layerswere collected, washed with a sodium thiosulfate solution (100 ml),brine (3×50 ml), dried and evaporated to furnish the crude5-alkyl-6-benzyl-3,4-dihydro-2-methylthiopyrimidin-4 one (2) as a solidpurified by crystallization.

[0039] Alternatively, according to methods B and C, potassium carbonate(4.2 mmoles) and the proper alkyl halide (4.4 mmoles) were added to asuspension containing 2-thiouracil derivative (4 mmoles) in anhydrousN,N-dimethylformamide (2 ml). The resulting mixture was stirred at roomtemperature (method B) or at 80° C. (method C) until starting materialdisappeared at the TLC control (silica gel; n-hexane:ethylacetate:methanol 12:3:1). Then the reaction content was poured on coldwater (200 mL), made acid (pH 5) with 0.5N acetic acid and extractedwith ethyl acetate (3×50 ml). The organic layers were collected, washedwith a sodium thiosulfate solution (100 ml), brine (100 ml), dried andevaporated to furnish5-alkyl-6-benzyl-3,4-dihydro-2-methylthiopyrimidin-4-ones (3) and (4) ascrude material which was then purified by column chromatography onsilica gel (eluent: n-hexane:ethyl acetate:methanol 12:3:1) followed bycrystallization. Physical and chemical data of representative compoundsof the invention are reported in table 1. Cytotoxicity and anti-HIV-1activity in vitro are reported in table 2.

[0040] Title derivatives were prepared according to the proceduredescribed for the synthesis of compounds with X═S (I), using ethylarylacetylalkylacetates and guanidine [2-amino-6-benzylpyrimidin-4-ones(5)] as starting materials. 2-Alkylaminoderivatives (6) were synthesizedby heating the previously reported5-alkyl-6-benzyl-3,4-dihydro-2-methylthio pyrimidin-4-ones with 20-30 mlof proper amine in a sealed tube at 170° C. for 24 h. Physical andchemical data of some compounds (6) are reported in table 1.Cytotoxicity and anti-HIVI activity in vitro are reported in table 2.The compounds of the present invention are useful in the inhibition ofHIV reverse transcriptase, the prevention or treatment of infection bythe human immunodeficiency virus (HIV) and the treatment of consequentpathological conditions such as AIDS. Treating AIDS or preventing ortreating infection by HIV is defined as including, but not limited to,treating a wide range of states of HIV infection: AIDS, ARC (AIDSrelated complex), both symptomatic and asymptomatic, and actual orpotential exposure to HIV. For example, the compounds of this inventionare useful in treating infection by HIV after suspected past exposure toHIV by, e.g., blood transfusion, organ transplant, exchange of bodyfluids, bites, accidental needle stick, or exposure to patient bloodduring surgery.

[0041] The compounds of this invention are also useful in thepreparation and execution of screening for antiviral compounds. Forexample, the compounds of this invention are useful for isolating enzymemutants, which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antiviral to HIVreverse transcriptase e.g., by competitive inhibition. Thus thecompounds of this invention are commercial products to be sold for thesepurposes. For inhibition of HIV reverse transcriptase, the prevention ortreatment of infection by HIV and the treatment of AIDS or ARC, thecompounds of the present invention may be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non toxic pharmaceutically-acceptable carriers, adjuvantsand vehicles. Thus, in accordance with the present invention there isfurther provided a method of treating and a pharmaceutical compositionfor treating HIV infection and AIDS. The treatment involvesadministering to a patient in need of such treatment a pharmaceuticalcomposition comprising a pharmaceutical carrier and a therapeuticallyeffective amount of a compound of the present invention. Thesepharmaceutical compositions may be in the form of orally administrablesuspensions or tablets; nasal sprays; sterile injectable preparations,for example, as sterile injectable aqueous or oleagenous suspensions orsuppositories.

[0042] When administered orally as a suspension, these compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants known in the art.

[0043] When administered by nasal aerosol or inhalation, thesecompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and may be prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,absorption promoters to enhance bioavailability, fluorocarbons, and/orother solubilizing or dispersing agents known in the art.

[0044] The injectable solutions or suspensions may be formulatedaccording to known art, using suitable non toxic, parenterallyacceptable diluents or solvents, such as mannitol, 1,3-butanediol,water, Ringer's solution or isotonic sodium chloride solution, orsuitable dispersing or wetting and suspending agents, such as sterile,bland, fixed oils, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0045] When rectally administered in the form of suppositories, thesecompositions may be prepared by mixing the drug with a suitablenon-irritating excipient; such as cocoa buffer, synthetic glyceride,esters or polyethylene glycols, which are solid at ordinarytemperatures, but liquidity and/or dissolve in the rectal cavity torelease the drug.

[0046] The compounds of this invention can be administered orally tohumans in a dosage range of 1 to 75 mg/kg body weight. One preferreddosage range is 1 to 50 mg/kg body weight orally. Another preferreddosage range is 5 to 75 mg/kg body weight orally. It will be understood,however, that the specific dose level and frequency of dosage for anyparticular patient may be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the age, bodyweight, general health, sex, diet, mode and time of administration, rateof excretion, drug combination, the severity of the particularcondition, and the host undergoing therapy.

[0047] The present invention is also directed to combinations of the HIVreverse transcriptase inhibitor compounds with one or more agents usefulin the treatment of AIDS. The D compounds of this invention can beadministered in combination with other compounds that are HIV reversetranscriptase inhibitors, and/or with compounds that are HIV proteaseinhibitors. When used in a combination treatment with compounds of theinstant invention, dosage levels of HIV protease inhibitors of the orderof 1 to 25 or 50 grams-per-day are useful in the treatment or preventionof the above-indicated conditions, with oral doses two-to-five timehigher. For example, infection by HIV is effectively treated by theadministration of from 5 to 25 milligrams of the HIV protease inhibitorper kilogram of body weight from one to three times per day.

[0048] It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy. Dosages ofHIV reverse transcriptase inhibitors, when used in a combinationtreatment with compounds of the present invention, are comparable tothose dosages specified above for the present compounds, it will beunderstood that the scope of combinations of the compounds of thisinvention with AIDS antivirals includes any combination with anypharmaceutical composition useful for the treatment of AIDS.

[0049] Antiviral Assay Procedures

[0050] Compounds. Compounds were solubilized in DMSO at 200 mM and thendiluted into culture medium.

[0051] Cells and viruses. MT-4, C8166, H9/IIIB and CEM cells were grownat 37° C. in a 5% CO₂ atmosphere in RPMI 1640 medium, supplemented with10% fetal calf serum (FCS), 100 IU/mL penicillin and 100 μg/mLstreptomycin. Cell cultures were checked periodically for the absence ofmycoplasma contamination with a MycoTect Kit (Gibco). Humanimmunodeficiency virus type-1 (HIV-1, III_(B) strain) was obtained fromsupernatants of persistently infected H9/III_(B) cells. HIV-1 stocksolution had a titres of 4.5×10⁶ 50% cell culture infectious dose(CCID₅₀)/ml.

[0052] HIV titration. Titration of HIV was performed in C8166 cells bythe standard limiting dilution method (dilution 1:2, four replica wellsper dilution) in 96-well plates. The infectious virus titre wasdetermined by light microscope scoring of cytopathicity after 4 days ofincubation and the virus titres were expressed as CCID₅₀/mL.

[0053] Anti-HIV assays. Activity of the compounds against HIV-1 andHIV-2 multiplication in acutely infected cells was based on theinhibition of virus-induced cytopathicity in MT-4 and C8166 cells,respectively. Briefly, 50 μL of culture medium containing 1×10⁴ cellswere added to each well of flat-bottom microtiter trays containing 50 μlof culture medium with or without various concentrations of the testcompounds. Then 20 μL of an HIV suspension containing 100 CCID₅₀ wereadded. After a 4-day incubation at 37° C., the number of viable cellswas determined by the3-(4,5-dimethylthiazol-1-yl)-2,5-diphenyltetrazolium bromide (MTT)method. Cytotoxicity of the compounds was evaluated in parallel withtheir antiviral activity. It was based on the viability of mock-infectedcells, as monitored by the MTT method.

[0054] RT assays. Assays were performed as follows. Briefly, purifiedrRT was assayed for its RNA-dependent polymerase-associated activity ina 50 μL volume containing: 50 mM TrisHCl (pH 7.8), 80 mM KCII, 6 mMMgC12, 1 mM DTT. 0.1 mg/mL BSA, 0.3 OD₂₆₀ unit/mL template:primer[poly(rC)-oligo(dG)12-18] and 10 μM [³H]dGTP (1 Ci/mmol). Afterincubation for 30 min at 37° C., the samples were spotted on glass fiberfilters (Whatman GF/A), and the acid-insoluble radioactivity wasdetermined.

EXAMPLES

[0055]2-Cyclopentylthio-6-(2,6-difluorophenylmethyl)-3,4-dihydrogyrimidin-4-(3H)-one(MC867).

[0056] A mixture of6-(2,6-difluorophenylmethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(0.16 g, 0.65 mmol; prepared as reported in scheme B), cyclopentylbromide (0.11 g, 0.08 mL., 0.71 mmol) and potassium carbonate (0.09 g,0.65 mmol) in 1 mL of anhydrous DMF was stirred at room temperature for24 h. After treatment with cold water (200 mL), the solution wasextracted with ethyl acetate (3×50 mL). The organic layers werecollected, washed with brine (3×50 mL), dried and evaporated to furnishcrude MC867, which was purified by chromatography on silica gel column(eluent: n-hexane/ethyl acetate/methanol 12/3/1).

[0057] Yield (%): 45; mp (CC): 168-169; recrystallization solvent:cyclohexane; formula (molecula-weight): C₁₆H₁₆F₂N₂OS (322.37).

[0058]2-Cyclopenlylthio-6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methylpyrimidin-4-(3H)-one(MC922).

[0059] The synthesis of MC922 was accomplished according to the abovereported procedure starting from6-(2,6-difluorophenylmethyl)-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin-4-(3H)-one(see scheme B).

[0060] Yield (%): 54; mp (° C.): 192-193; recrystallization solvent:cyclohexane; formula (molecular weight): C₁₇H₁₈F₂N₂OS (336.40).

[0061]2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydropyrimidin-4-(3H-one(MC1008)

[0062] The synthesis of MC1008 was accomplished according to the abovereported procedure starting from6-[1-(2,6-difluorophenyl)ethyl]-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(see scheme B).

[0063] Yield (%): 54; mp (° C.): 165.5-166.5; recrystallization solvent:cyclohexane; formula (molecular weight): C₁₇H₁₈F₂N₂OS (336.40).

[0064]2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin4(3H-one(MC1047)

[0065] The synthesis of MC1047 was accomplished according to the abovereported procedure, starting from6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(see scheme B).

[0066] Yield (%): 60; mp (° C.): 196-197; recrystallization solvent:cyclohexane; formula (molecular weight): CH₁₈F₂N₂OS (350.43).

[0067]6-(2,6-DifluoroPhenylmethyl)-3,4-dihydro-2-(methylthiomethylthiopyrimidin-4-(3H)-one(MC1161)

[0068] The synthesis of MC1161 was accomplished according to the abovereported procedures, starting from6-(2,6-difluorophenylmethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(see scheme B) and chloromethyl methyl sulfide.

[0069] Yield (%): 72; mp (° C.): 159-160; recrystallization solvent:benzene/cyclohexane; formula (molecular weight): C₁₃H₁₂F₂N₂OS, (314.37).

[0070]6-(2,6-Difluorophenylmethyl)-3,4-dihydro-5-methyl-2-(methylthiomethyl)thiopyrimidin-4(3H)-one(MC1162).

[0071] The synthesis of MC1162 was accomplished according to the abovereported procedure, starting from6-(2,6-difluorophenylmethyl)-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin4(3H)-one (see scheme B) and chloromethyl methyl sulfide.

[0072] Yield (%): 70; mp (° C.): 183-184; recrystallization solvent:benzene/cyclohexane; formula (molecular weight): C₁₄H₁₄F₂N₂OS, (328.39).

[0073]6-(2,6-Difluorophenylmethyl)-3,4-dihydro-5-(1-methylethyl)-2-(methylthiomethyl)thiopyrimidin-4-(3H)-one MC1145).

[0074] The synthesis of MC1145 was accomplished according to the abovereported procedure, starting from6-(2,6-difluorophenylmethyl)-5-(1-methylethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(see scheme B) and chloromethyl methyl sulfide.

[0075] Yield (%): 62; mp (° C.): 158.5-160; recrystallization solvent:cyclohexane; formula (molecular weight): C₁₆H₁₈F₂N₂OS₂ (356.45).

[0076]2-Cyclopenltylamino-6-(2,6-difluorophenylmethyl)-3,4-dihydropyrimidin-4-(3H)-one(MC1022).

[0077] Cyclopentylamine (10 mL) was heated while stirring with6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4-(3H)-one(0.30 g, 1.12 mmol; prepared as reported in scheme B or C) in a sealedtube at 160° C. for 10 h. After cooling, the mixture was diluted withwater (200 mL) and extracted with ethyl acetate (3×50 mL). The organiclayers were collected, washed with brine (3×50 mL), dried and evaporatedto furnish crude MC1022, which was purified by chromatography on silicaget column (eluent: ethyl acetate/chloroform 1/1).

[0078] Yield (%): 74; mp (° C.):—(oil); formula (molecular weight):C₁₆H₁₇F₂N₃O (305.33).

[0079]2-Cyclopentylamino-6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methylpyrimidin-4-(3H-one(MC1050).

[0080] The synthesis of MC1050 was accomplished according to the abovereported procedure, starting from6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidirin-4(3H)-one(see scheme B or C).

[0081] Yield (%): 60: mp (° C.): 115-117; recrystallization solvent:n-hexane/cyclohexane; formula (molecular weight): C₁₇H₁₉F₂N₃O (319.35).

[0082]2-Cyclopentylamino-6-[1-(2,6-difluorophenylethyl]-3,4-dihydropyrimidin-4-(3H-one(MC1048).

[0083] The synthesis of MC1048 was accomplished according to the abovereported procedure, starting from6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one(see scheme B or C).

[0084] Yield (%): 48; mp (° C.):—(oil); formula (molecular weight)C₁₇H₁₉F₂N₃O (319.35).

[0085]2-Cyclopentylamino-6-[1-(2,6-difluorophenylethyl]-3,4-dihydro-5-methylpyrimidin-4-(3H)one(MC1129)

[0086] The synthesis of MC1129 was accomplished according to the abovereported procedure, starting from6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4(3H)-one(see scheme B or C).

[0087] Yield (%): 38; mp (° C.):—(oil); formula (molecular weight):C₁₈H₂₁F₂N₃O (333.38).

[0088]6-(2,6-Difluorophenylmethyl)-3,4-dihydro-2-(4-thiomorpholin-1-yl)pyrimidin-4-(3H)-one(MCI 193).

[0089] The synthesis of MC1193 was accomplished according to the abovereported procedure, starting from thiomorpholine and6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one(see scheme B or C).

[0090] Yield (%): 78; mp (° C.): 233-234; recrystallization solvent:acetonitrile; formula (molecular weight): C₁₅H₁₆F₂N₃OS (323.36).

[0091]6-(2,6-Difluorophenylmethyl)-3,4-dihydro-2-N,N-dimethylaminopyrimidin-4-(3H)-one(MCI 182).

[0092] To a stirred solution of sodium metal (0.14 g, 6.3 mg-atoms) inabsolute ethanol (50 mL) 1,1-dimethylguanidine sulfate (1.17 g, 4.3mmol) and ethyl 4-(2,6-difluorophenyl)acetylacetate (0.76 g, 3.15 mmol)were successively added. The mixture was heated while stirring at refluxfor 8 h. After cooling, the solvent was distilled in vacuo at 40-50° C.until dryness and the residue was dissolved in water (200 mL) and madeacid (pH 5) with 0.5N acetic acid. The resulting precipitate (the crudeisocytosine derivative) was filtered under reduced pressure, washed withdiethyl ether, vacuum dried at 80° C. for 12 h and then crystallizedfrom benzene/cyclohexane (see scheme C starting from ethyl4-(2,6-difluorophenyl)acetylacetate and replacing guanidinehydrochloride with 1,1-dimethylguanidine sulfate).

[0093] Yield (%): 88; mp (° C.): 210-211; recrystallization solvent:benzene/cyclohexane; formula (molecular weight): C₁₃H₁₃F₂N₃O (265.26).TABLE 1 Physical and Chemical Data of MC Compounds

Compd X Y Z R R¹ R² R³ R⁴ R⁵ m.p., ° C. Recryst. Solvent % yieldFormula^(a) MC 507 O H H 2,5-Me₂-c-hex H H H H H 130-132 Petrol.Ether/diethyl ether 22 C₁₉H₂₄N₂O₂ MC 508 O H H 4,5-Me₂-c-hex H H H H H132-134 Petrol. Ether/diethyl ether 28 C₁₉H₂₄N₂O₂ MC 512 O H H3,5-Me₂-c-hex H H H H H 178-181 Petrol. Ether/diethyl ether 12C₁₉H₂₄N₂O₂ MC 531 O Me H 2,5-Me₂-c-hex H H H H H 196-198 Petrol.Ether/diethyl ether 18 C₂₀H₂₆N₂O₂ MC 1114 O H H Sec-but F H H H F 87-88Petrol. Ether/diethyl ether 28 C₁₅H₂₆F₂N₂O₂ MC 1103 O H H c-pent F H H HF 183.5-184.5 Benzene 52 C₁₆H₁₈F₂N₂O₂ MC 843 S H H benzyloxymeth H H H HH 181-183 Cyclohexane/benzene 38 C₁₉H₁₈N₂O₂S MC 796 S H Ph Sec-but H H HH H 157-158 n-hexane/cyclohexane 78 C₂₄H₂₂N₂OS MC 890 S H Me iso-prop HH H H H 118-119 n-hexane 88 C₁₅H₁₈N₂OS MC 892 S H Me c-pent H H H H H95-96 n-hexane 65 C₁₇H₂₁N₂OS MC 898 S H Me c-hex H H H H H 142-143n-hexane 59 C₁₈H₂₂N₂OS MC 899 S H Et Iso-prop H H H H H 144-145Cyclohexane 85 C₁₆H₁₉N₂OS MC 900 S H Et c-pent H H H H H 168-169Cyclohexane 69 C₁₈H₂₂N₂OS MC 903 S H Et c-hex H H H H H 175.5-176.5Cyclohexane 60 C₁₉H₂₄N₂OS MC 806 S H H Sec-but Me H H H H 118-119n-hexane/cyclohexane 67 C₁₈H₂₀N₂OS MC 842 S H H c-pent Me H H H H142-144 Cyclohexane 61 C₁₇H₂₀N₂OS MC 809 S H H Sec-but H H Me H H107.5-108.5 n-hexane 56 C₁₆H₂₀N₂OS MC 817 S H H Sec-but NO₂ H H H H148.0-148.5 Cyclohexane/benzene 68 C₁₅H₁₇N₃O₃S MC 897 S H H Sec-but HNO₂ H H H 127-128 Cyclohexane/benzene 54 C₁₅H₁₇N₃O₃S MC 863 S H HSec-but H H NO₂ H H 128-130 Petrol. Ether/diethyl ether 100 C₁₅H₁₇N₃O₃SMC 854 S H H Sec-but Cl H H H H 120-121 n-hexane/cyclohexane 58C₁₅H₁₇N₃O₃S MC 857 S H H Sec-but H Cl H H H 98-99 Cyclohexane 92C₁₅H₁₇N₃O₃S MC 859 S H H Sec-but H H Cl H H 125-126 Cyclohexane 74C₁₃H₁₇ClN₂OS MC 880 S H H Sec-but F H H H H 106-107 n-hexane/cyclohexane68 C₁₅H₁₇ClN₂OS MC 884 S H H Sec-but H F H H H 96-97 Cyclohexane 67C₁₅H₁₇FN₂OS MC 889 S H H Sec-but H H F H H 98-99 n-hexane 94 C₁₅H₁₇FN₂OSMC 825 S H H Sec-but NH₂ H H H H 143-144 Cyclohexane/benzene 74C₁₅H₁₉N₃OS MC 960 S H H Sec-but H H NH₂ H H 128-130 Cyclohexane 77C₁₅H₁₉N₃OS MC 868 S H H Sec-but CF₃ H H H H 125-126 Cyclohexane 89C₁₆H₁₇F₃N₂OS MC 950 S H H Sec-but H H CF₃ H H 144-145 Cyclohexane 75C₁₆H₁₇F₃N₂OS MC 952 S H H Sec-but OMe H H H H 123-124 Cyclohexane 69C₁₆H₂₀N₂O₂S MC 957 S H H Sec-but H OMe H H H 78-80 n-hexane/Cyclohexane71 C₁₆H₂₀N₂O₂S MC 964 S H H Sec-but H H OMe H H 112-113 Cyclohexane 63C₁₆H₂₀N₂O₂S MC 1041 S H H Sec-but H F H H H 122-123 Cyclohexane 68C₁₅H₁₆F₂N₂OS MC 1042 S H H Sec-but H Me H H H 119-120 n-hexane 72C₁₇H₂₂N₂OS MC 877 S H H Me Cl H H H Cl 237-238 benzene 98 C₁₂H₁₄Cl₂N₂OSMC 878 S H H iso-prop Cl H H H Cl 230-231 benzene 81 C₁₄H₁₄Cl₂N₂OS MC856 S H H n-but Cl H H H Cl 153-154 cyclohexane 62 C₁₅H₁₆Cl₂N₂OS MC 885S H H iso-but Cl H H H Cl 143.5-144.5 cyclohexane 56 C₁₅H₁₆Cl₂N₂OS MC815 S H H sec-but Cl H H H Cl 183-184 cyclohexane/benzene 55C₁₅H₁₆Cl₂N₂OS MC 888 S H H c-pent Cl H H H Cl 185-186 cyclohexane 54C₁₆H₁₆Cl₂N₂OS MC 891 S H H c-hex Cl H H H Cl 200-201 cyclohexane/benzene49 C₁₇H₁₈Cl₂N₂OS MC 871 S H H Me F H H H F 197-198 benzene 95C₁₂H₂₀F₂N₂OS MC 860 S H H iso-prop F H H H F 174-175 cyclohexane 74C₁₄H₁₄F₂N₂OS MC 872 S H H n-but F H H H F 126-127 cyclohexane 46C₁₅H₁₆F₂N₂OS MC 866 S H H iso-but F H H H F 136-137 cyclohexane 49C₁₅H₁₆F₂N₂OS MC 848 S H H sec-but F H H H F 149-150 n-hexane/cyclohexane48 C₁₅H₁₆F₂N₂OS MC 867 S H H c-pent F H H H F 168-169 cyclohexane 45C₁₆H₁₆FN₂OS MC 870 S H H c-hex F H H H F 164-165 cyclohexane 40C₁₇H₁₈F₂N₂OS MC 1001 S H Me iso-prop Cl H H H Cl   196-196.5cyclohexane/benzene 52 C₁₅H₁₆Cl₂N₂OS MC 996 S H Me c-pent Cl H H H Cl181-182 cyclohexane 45 C₁₇H₁₈Cl₂N₂OS MC 1016 S H Me c-hex Cl H H H Cl211-212 cyclohexane/benzene 42 C₁₈H20Cl₂N₂OS MC 1000 S H Et iso-prop ClH H H Cl 166-168 diethyl ether 54 C16H₁₈Cl₂N₂OS MC 1002 S H Et c-pent ClH H H Cl 168-169 diethyl ether 40 C₁₈H₂₀Cl₂N₂OS MC 1003 S H Et c-hex ClH H H Cl 198-199 cyclohexane 41 C₁₉H₂₂Cl₂N₂OS MC 1007 S H Me iso-prop FH H H F 155-156 cyclohexane 53 C₁₅H₁₆F₂N₂OS MC 1044 S H Me iso-but F H HH F 159-160 cyclohexane 49 C₁₆H₁₆F₂N₂OS MC 1045 S H Me n-but F H H H F149-150 cyclohexane 58 C₁₆H₁₆F₂N₂OS MC 1110 S H Me sec-but F H H H F133-134 n-hexane 75 C₁₆H₁₆F₂N₂OS MC 1008 S H Me c-pent F H H H F165.5-166.5 cyclohexane 60 C₁₇H₁₈F₂N₂OS MC 1013 S H Me c-hex F H H H F206-207 benzene 44 C₁₈H₂₀F₂N₂OS MC 1005 S H Et iso-prop F H H H F149-150 cyclohexane 40 C₁₆H₁₈F₂N₂OS MC 1006 S H Et c-pent F H H H F141-143 cyclohexane 45 C₁₆H₂₀F₂N₂OS MC 1014 S H Et c-pent F H H H F154-155 cyclohexane 51 C₁₉H₂₂F₂N₂OS MC 971 S H Me iso-prop CH═CH— H H H161-162 n-hexane/cyclohexane 58 C₁₉H₂₀N₂OS CH═CH MC 972 S H Me c-pentCH═CH— H H H 140-141 n-hexane/cyclohexane 49 C₂₁H₂₂N₂OS CH═CH MC 974 S HMe c-hex CH═CH— H H H 177-178 n-hexane 45 C₂₂H₂₄N₂OS CH═CH MC 969 S H Etiso-prop CH═CH— H H H 163-164 cyclohexane 54 C₂₀H₂₂N₂OS CH═CH MC 973 S HEt c-pent CH═CH— H H H oil — 48 C₂₂H₂₄N₂OS CH═CH MC 975 S H Et c-hexCH═CH— H H H 126-127 n-hexane 41 C₂₃H₂₆N₂OS MC 844 S Me H sec-but Me H HH H 177-178 cyclohexane 55 C₁₇H₂₂N₂OS MC 845 S Me H sec-but H H Me H H127-128 n-hexane 61 C₁₇H₂₂N₂OS MC 925 S Me H sec-but H NO₂ H H H 163-164cyclohexane/benzene 88 C₁₆H₁₉N₃O₃S MC 924 S Me H sec-but H H NO₂ H H178-180 cyclohexane/benzene 100 C₁₆H₁₉N₃O₃S MC 909 S Me H sec-but Cl H HH H 170-171 cyclohexane 68 C₁₆H₁₉ClN₂OS MC 910 S Me H sec-but H Cl H H H145-146 cyclohexane 75 C₁₆H₁₉ClN₂OS MC 911 S Me H sec-but H H Cl H H163-165 cyclohexane 79 C₁₆H₁₉ClN₂OS MC 913 S Me H sec-but F H H H H120.5-121.5 cyclohexane 65 C₁₆H₁₉FN₂OS MC 918 S Me H sec-but H F F H H146-147 cyclohexane 72 C₁₆H₁₆FN₂OS MC 919 S Me H sec-but H H H H H154-155 cyclohexane 69 C₂₆H₂₉FN₂OS MC 912 S Me H Me Cl H H H Cl 206-261benzene 93 C₃₀H₄₂Cl₂N₂OS MC 914 S Me H iso-prop Cl H H H Cl 241-242cyclohexane/benzene 78 C₂₅H₂₆Cl₂N₂OS MC 920 S Me H n-but Cl H H H Cl179-180 cyclohexane 52 C₁₆H₁₉Cl₂N₂OS MC 916 S Me H iso-but Cl H H H Cl208-209 cyclohexane 63 C₂₆H₂₈Cl₂N₂OS MC 850 S Me H sec-but Cl H H H Cl204-205 cyclohexane 53 C₁₆H₁₉Cl₂N₂OS MC 915 S Me H c-pent Cl H H H Cl252-253 cyclohexane/benzene 49 C₁₇H₁₈Cl₂N₂OS MC 917 S Me H c-hex Cl H HH Cl 237-238 cyclohexane 48 C₁₆H₁₉Cl₂N₂OS MC 869 S Me H Me F H H H F218.5-219.5 benzene 92 C₁₃H₁₂F₂N₂OS MC 881 S Me H iso-prop F H H H F164-165 cyclohexane 76 C₁₅H₂₆F₂N₂OS MC 905 S Me H n-but F H H H F178-179 cyclohexane 65 C₁₆H₁₈F₂N₂OS MC 921 S Me H iso-but F H H H F161-162 cyclohexane 59 C₁₆H₁₈F₂N₂OS MC 849 S Me H sec-but F H H H F128-129 n-hexane 49 C₁₆H₁₈F₂N₂OS MC 922 S Me H c-pent F H H H F 192-193cyclohexane 54 C₁₇H₁₈F₂N₂OS MC 923 S Me H c-hex F H H H F 191-192cyclohexane 49 C₁₈H₂₀F₂N₂OS MC 1060 S Me Me Me F H H H F 202-203cyclohexane/benzene 49 C₁₄H₁₄F₂N₂OS MC 1109 S Me Me sec-but F H H H F135-136 cyclohexane 55 C₁₇H₂₀F₂N₂OS MC 1047 S Me Me c-pent F H H H F196-197 cyclohexane 60 C₁₈H₂₀F₂N₂OS MC 798 S Et H sec-but H H H H H140-141 n-hexane 47 C₁₇H₂₂N₂OS MC 1037 S Et H iso-prop F H H H F 174-175benzene 78 C₁₆H₁₈F₂N₂OS MC 1038 S Et H sec-but F H H H F 150-151n-hexane/cyclohexane 82 C₁₇H₂₀F₂N₂OS MC 804 S Et H sec-but CH═CH— H H H198.5-199.5 cyclohexane 42 C₂₁H₂₄N₂OS CH═CH MC 1039 S i-pro H iso-prop FH H H F 167-168 n-hexane 76 C₁₇H₂₀F₂N₂OS MC 852 S allyl H sec-but H H HH H 127.5-128.5 cyclohexane 68 C₁₆H₂₂N₂OS MC 856 S n-pro H sec-but H H HH H 108-109 n-hexane 42 C₁₈H₂₄N₂OS MC 834 S n-but H sec-but H H H H Hoil — 32 C₁₉H₂₉N₂OS MC 1119 NH H H ethyl F H H H F 138-140n-hexane/cyclohexane 50 C₁₃H₁₃F₂N₂O MC 1078 NH H H n-prop F H H H F136-137 cyclohexane 49 C₁₅H₁₅F₂N₂O MC 979 NH H H iso-prop F H H H F150-151 diethyl ether 58 C₁₄H₁₅F₂N₂O MC 980 NH H H c-prop F H H H F183-184 cyclohexane/benzene 68 C₁₄H₁₃F₂N₃O MC 1077 NH H H n-but F H H HF 130-131 n-hexane 60 C₁₅H₁₇F₂N₃O MC 945 NH H H sec-but F H H H F140-141 diethyl ether 80 C₁₅H₁₇F₂N₃O MC 1043 NH H H MeOethyl F H H H F120-121 acetonitrile 78 C₁₄H₁₅F₂N₃O₂ MC 1022 NH H H c-pent F H H H F oil— 74 C₁₆H₁₇F₂N₂O MC 1049 NH H H c-hex F H H H F 143-144 diethyl ether 45C₁₇H₁₉F₂N₂O MC 1048 NH H Me c-pent F H H H F oil — 48 C₁₇FH₁₉F2N₃O MC1118 NH Me H iso-prop F H H H F 165-166 n-hexane 53 C₁₅H₁₇F₂N₂O MC 1130NH Me H sec-but F H H H F oil — 56 C₁₆H₁₉F₂N₃O MC 1050 NH Me H c-pent FH H H F 115-117 n-hexane/cyclohexane 60 C₁₇H₁₉F₂N₂O MC 1105 NH Me Hbenzyl F H H H F 182-183 cyclohexane/benzene 82 C₁₉H₁₇F₂N₃O MC 1129 NHMe Me c-pent F H H H F oil — 38 C₁₆H₂₁F₂N₂O MC 1167 NH H H Me F H H H F202-203 acetonitrile 39 C₁₂H₁₄F₂N₂O MC 1168 NH Me H Me F H H H F 210-211acetonitrile 48 C₁₃H₁₃F₂N₂O MC 1186 NH Me H n-prop F H H H F 156-157acetonitrile 62 C₁₅H₁₇F₂N₃O MC 1185 NH Me H n-but F H H H F 192-193acetonitrile 68 C₁₆H₁₉F₂N₃O MC 1178 NH H Me Me F H H H F 145-146acetonitrile 34 C₁₃H₁₃F₂N₃O MC 1190 NH H Me n-prop F H H H F oil — 45C₁₅H₁₇F₂N₃O MC 1191 NH H Me iso-prop F H H H F oil — 54 C₁₅H₁₇F₂N₃O MC1189 NH H Me n-but F H H H F oil — 55 C₁₆H₁₉F₂N₂O MC 1192 NH H Mesec-but F H H H F oil — 59 C₁₆H₁₉F₂N₂O MC 1180 NH H Me c-hex F H H H Foil — 62 C₁₈H₂₁F₂N₃O MC 1170 NH Me Me Me F H H H F 193-194cyclohexane/benzene 34 C₁₄H₁₅F₂N₃O MC 1187 NH Me Me n-but F H H H F oil— 49 C₁₇H₂₁F₂N₂O MC 1181 NH Me Me c-hex F H H H F oil — 54 C₁₉H₂₂F₂N₃OMC 1182 N H H Me₂ F H H H F 210-211 cyclohexane/benzene 88 C₁₃H₁₅F₂N₂OMC 1183 N H H Me-piperaz F H H H F 195-196 acetonitrile 84 C₁₆H₁₈F₂N₄OMC 1188 N H H morph F H H H F 215-216 acetonitrile 75 C₁₅H₁₅F₂N₃O₂ MC1193 N H H thiomorph F H H H F 233-234 acetonitrile 78 C₁₅H₁₅F₂N₂OS MC1194 N H H piperid F H H H F 209-210 acetontrile 68 C₁₆H₁₇F₂N₃O MC 1196N H H pyrrolid F H H H F 233-234 acetontrile 52 C₁₅H₁₅F₂N₃O MC 1202 N HH Et₂ F H H H F 159-160 acetontrile 43 C₁₅H17F₂N₃O MC 1204 N H H(n-prop)₂ F H H H F 111-112 n-hexane 32 C₁₇H₂₁F₂N₃O MC 1195 N Me H Me₂ FH H H F 237-238 acetonitrile 80 C₁₄H₁₅F₂N₃O MC 1203 N Me H Me₂ F H H H F235-236 acetonitrile 62 C₁₇H₁₈F₂N₄O MC 1205 N Me H morph F H H H F244-245 acetonitrile 65 C₁₆H₁₇F₂N₃O₂ MC 1206 N Me H thiomorph F H H H F255-256 acetonitrile 54 C₁₆H₁₇F₂N₄OS MC 1137 S Me Me iso-prop F H H H F177-178 n-hexane/cyclohexane 45 C₁₆H₁₈F₂N₂OS MC 1175 S Me Me n-but F H HH F 122-123 n-hexane 51 C₁₇H₁₈F₂N₂OS MC 1153 S Me Me iso-but F H H H F152-153 cyclohexane 58 C₁₇H₂₀F₂N₂OS MC 1174 S Me Me c-hex F H H H F208-209 n-hexane/cyclohexane 48 C₁₉H₂₂F₂N₃OS MC 1161 S H H MeSMe F H H HF 159-160 cyclohexane/benzene 72 C₁₃H₁₂F₂N₂OS₂ MC 1162 S Me H MeSMe F HH H F 183-184 cyclohexane/benzene 70 C₁₄H₁₄F₂N₂OS₂ MC 1157 S Et H MeSMeF H H H F 153-154 cyclohexane 69 C₁₅H₁₆F₂N₂OS₂ MC 1145 S i-pro H MeSMe FH H H F 158.5-160   cyclohexane 62 C₁₆H₁₈F₂N₃OS₂ MC 1140 S H H MeSMe H HH H H 117.5-118   n-hexane 64 C₁₃H₁₄N₂OS₂

[0094] TABLE 2 Cytotoxicity and anti-HIV-1 Activity of MC Compounds. (A)

[μM] Compd. X Y Z R R¹ R² R³ R⁴ R⁵ CC₅₀ ^(b) EC₅₀ ^(c) SI^(d) MC 507 O HH 2,5-Me₂-c-hex H H H H H 143 3.5 40 MC 508 O H H 4,5-Me₂-c-hex H H H HH 58 6.4 9 MC 512 O H H 3,5-Me₂-c-hex H H H H H >200 30 >6.7 MC 531 O MeH 2,5-Me₂-c-hex H H H H H 138 3.5 39 MC 1114 O H H sec-but F H H H F 13025 52 MC 1103 O H H c-pent F H H H F >200 20 >10 MC 843 S H Hbenzyloxymethyl H H H H H >200 45 >4 MC 796 S H Ph sec-but H H H H H61 >61 — MC 890 S H Me iso-prop H H H H H >200 .9 >222 MC 892 S H Mec-pent H H H H H 159 .6 333 MC 898 S H Me c-hex H H H H H 149 .6 248 MC899 S H Et iso-prop H H H H H 200 .8 250 MC 900 S H Et c-pent H H H HH >200 1.0 >200 MC 903 S H Et c-hex H H H H H >200 1.3 >154 MC 806 S H Hsec-but Me H H H H >200 1.8 >111 MC 842 S H H c-pent Me H H H H >2003.4 >59 MC 809 S H H sec-but H H Me H H 200 0.6 333.3 MC 817 S H Hsec-but NO₂ H H H H >200 0.25 >800 MC 897 S H H sec-but H NO₂ H H H 1570.40 392 MC 863 S H H sec-but H H NO₂ H H 151 1.5 101 MC 854 S H Hsec-but Cl H H H H 200 1 200 MC 857 S H H sec-but H Cl H H H 116 2 58 MC859 S H H sec-but H H Cl H H 120 5 24 MC 880 S H H sec-but F H H H H 2000.26 769 MC 884 S H H sec-but H F H H H >200 0.7 >286 MC 889 S H Hsec-but H H F H H >200 8.7 23 MC 825 S H H sec-but NH₂ H H H H >20021.2 >9 MC 960 S H H sec-but H H NH₂ H H >200 23 >8 MC 868 S H H sec-butCF₃ H H H H >200 32 6.2 MC 959 S H H sec-but H H CF₃ H H 200 25 8 MC 952S H H sec-but OMe H H H H >200 1.96 >208 MC 957 S H H sec-but H OMe H HH >200 1.2 >166 MC 964 S H H sec-but H H OMe H H 147 14 10.5 MC 1041 S HH sec-but H F H F H >200 1.4 >143 MC 1042 S H H sec-but H Me H Me H 1330.6 222 MC 877 S H H Me Cl H H H Cl >200 3.2 >62 MC 878 S H H iso-propCl H H H Cl >200 1.9 >105 MC 886 S H H n-but Cl H H H Cl >200 0.44 >454MC 885 S H H iso-but Cl H H H Cl >200 0.45 >444 MC 815 S H H sec-but ClH H H Cl >200 0.14 >1,428 MC 888 S H H c-pent Cl H H H Cl >200 0.4 >500MC 891 S H H c-hex Cl H H H Cl >200 0.6 >333 MC 871 S H H Me F H H H F200 0.81 247 MC 860 S H H iso-prop F H H H F >200 0.2 >1,000 MC 872 S HH n-but F H H H F 162 0.18 900 MC 866 S H H iso-but F H H H F 182 0.141,300 MC 848 S H H sec-but F H H H F 200 0.04 5,000 MC 867 S H H c-pentF H H H F >200 0.08 >2,500 MC 870 S H H c-hex F H H H F 200 0.08 2,500MC 1001 S H Me iso-prop Cl H H H Cl 117 1.2 97.5 MC 996 S H Me c-pent ClH H H Cl 78.3 1.0 78.3 MC 1016 S H Me c-hex Cl H H H Cl >200 2.9 >69 MC1000 S H Et iso-prop Cl H H H Cl >200 0.4 >500 MC 1002 S H Et c-pent ClH H H Cl 23.4 1.0 23.4 MC 1003 S H Et c-hex Cl H H H Cl >200 3.6 >55.5MC 1007 S H Me iso-prop F H H H F 167 0.05 3,340 MC 1044 S H Me iso-butF H H H F >200 0.05 >4,000 MC 1045 S H Me n-but F H H H F >200 0.072,857 MC 1110 S H Me sec-but F H H H F >200 0.03 >6,666 MC 1008 S H Mec-pent F H H H F >200 0.03 >6,666 MC 1013 S H Me c-hex F H H H F >2000.16 >1,250 MC 1005 S H Et iso-prop F H H H F 70 0.08 875 MC 1006 S H Etc-pent F H H H F 200 0.15 1,333 MC 1014 S H Et c-hex F H H H F 130 0.052,600 MC 971 S H Me iso-prop CH═CH— H H H 119 1.1 108 CH═CH MC 972 S HMe c-pent CH═CH— H H H 93 0.5 186 CH═CH MC 974 S H Me c-hex CH═CH— H H H45 0.14 321.4 CH═CH MC 969 S H Et iso-prop CH═CH— H H H 50 1.5 33.3CH═CH MC 973 S H Et c-pent CH═CH— H H H 51 3.0 17 CH═CH MC 975 S H Etc-hex CH═CH— H H H 16.9 0.18 94 CH═CH MC 844 S Me H sec-but Me H H HH >200 1.7 >118 MC 845 S Me H sec-but H H Me H H 26 0.8 32 MC 925 S Me Hsec-but H NO₂ H H H >200 0.35 >571 MC 924 S Me H sec-but H H NO₂ HH >200 2 >100 MC 909 S Me H sec-but Cl H H H H >200 0.27 >741 MC 910 SMe H sec-but H Cl H H H >200 0.96 >208 MC 911 S Me H sec-but H H Cl HH >200 9.5 20 MC 913 S Me H sec-but F H H H H 140 0.41 341 MC 918 S Me Hsec-but H F H H H >200 1.2 >166 MC 919 S Me H sec-but H H F H H 105 119.5 MC 912 S Me H Me Cl H H H Cl >200 3.2 >62 MC 914 S Me H iso-prop ClH H H Cl >200 1.3 >154 MC 920 S Me H n-but Cl H H H Cl >200 1.17 >171 MC916 S Me H iso-but Cl H H H Cl >200 1.2 >166 MC 850 S Me H sec-but Cl HH H Cl >200 0.05 >4,000 MC 915 S Me H c-pent Cl H H H Cl >200 1.8 >111MC 917 S Me H c-hex Cl H H H Cl >200 22 >9 MC 869 S Me H Me F H H H F200 0.19 1,053 MC 881 S Me H iso-prop F H H H F >200 0.05 >4,000 MC 905S Me H n-but F H H H F >200 0.08 >2,500 MC 921 S Me H iso-but F H H H F64 0.1 640 MC 849 S Me H sec-but F H H H F 80 0.001 8,000 MC 922 S Me Hc-pent F H H H F >200 0.08 >2,500 MC 923 S Me H c-hex F H H H F >2000.09 >2,222 MC 1060 S Me Me Me F H H H F >200 0.04 >5,000 MC 1109 S meMe sec-but F H H H F 200 0.03 6,666 MC 1047 S Me Me c-pent F H H HF >200 0.009 >22,222 MC 798 S Et H sec-but H H H H H >200 1.0 >200 MC1037 S Et H iso-prop F H H H F 65 0.2 326 MC 1038 S Et H sec-but F H H HF >200 0.1 >2,000 MC 804 S Et H sec-but CH═CH— H H H >200 5.3 >34 CH═CHMC 1039 S iso-prop H iso-prop F H H H F >200 0.4 >500 MC 852 S allyl Hsec-but H H H H H >200 3 >67 MC 856 S n-prop H sec-but H H H H H 190 1216 MC 834 S n-but H sec-but H H H H H >200 >200 — MC 1119 NH H H ethyl FH H H F >200 0.8 >250 MC 1078 NH H H n-prop F H H H F 200 0.11 1,818 MC979 NH H H iso-prop F H H H F >200 0.38 >526 MC 980 NH H H c-prop F H HH F >200 3.17 >63 MC 1077 NH H H n-but F H H H F 100 0.10 1,000 MC 945NH H H sec-but F H H H F >200 0.13 >1,540 MC 1043 NH H H MeOethyl F H HH F >200 0.8 >250 MC 1022 NH H H c-pent F H H H F >200 0.09 >2,222 MC1049 NH H H c-hex F H H H F 66 0.14 471 MC 1048 NH H Me c-pent F H H H F75 0.03 2,500 MC 1118 NH Me H iso-prop F H H H F 190 0.03 6,333 MC 1130NH Me H sec-but F H H H F 200 0.07 2,857 MC 1050 NH Me H c-pent F H H HF >200 0.02 >10,000 MC 1105 NH Me H benzyl F H H H F 50 0.50 100 MC 1129NH Me H c-pent F H H H F 90 0.02 4,500 MC 1187 NH H H Me F H H H F >2001.5 >133 MC 1168 NH Me H Me F H H H F 135 0.4 335 MC 1186 NH Me H n-propF H H H F >200 0.02 >10,000 MC 1185 NH Me H n-but F H H H F >2000.02 >10,000 MC 1178 NH H Me Me F H H H F 106 0.11 964 MC 1190 NH H Men-prop F H H H F 103 0.02 5,150 MC 1191 NH H Me iso-prop F H H H F 1150.03 3,830 MC 1189 NH H Me n-but F H H H F 52 0.03 1,730 MC 1192 NH H Mesec-but F H H H F 86 0.04 2,150 MC 1180 NH H Me c-hex F H H H F 56 0.022,545 MC 1170 NH Me Me Me F H H H F 200 0.03 >6,666 MC 1187 NH Me Men-but F H H H F 83 0.01 8,300 MC 1181 NH Me Me c-hex F H H H F 58 0.032,231 MC 1182 N H H Me₂ F H H H F >200 0.05 >4,000 MC 1183 N H HMe-piperaz F H H H F >200 7.1 >28 MC 1188 N H H morph F H H H F >2000.6 >333 MC 1193 N H H thiomorph F H H H F >200 0.05 >4,000 MC 1194 N HH piperid F H H H F >200 0.02 >10,000 MC 1196 N H H pyrrolid F H H HF >200 2.1 >95 MC 1202 N H H Et₂ F H H H F >200 0.26 >769 MC 1204 N H H(n-prop)₂ F H H H F >200 3.8 >53 MC 1195 N Me H Me₂ F H H H F >2000.02 >10,000 MC 1203 N Me H Me-piperaz F H H H F >200 0.36 >555 MC 1205N Me H morph F H H H F >200 0.047 >4,255 MC 1206 N Me H thiomorph F H HH F >200 0.09 >2,222 MC 1137 S Me Me iso-prop F H H H F 200 0.007 28,571MC 1175 S Me Me n-but F H H H F 112 0.008 14,000 MC 1153 S Me Me iso-butF H H H F >200 0.01 >20,000 MC 1174 S Me Me c-hex F H H H F >2000.018 >1,111 MC 1047+ S Me Me c-pent F H H H F >200 0.002 >100,000 MC1047− S Me Me c-pent F H H H F >200 0.7 >286 MC 1161 S H H MeSMe F H H HF >200 0.80 >250 MC 1162 S Me H MeSMe F H H H F 30 0.12 250 MC 1157 S EtH MeSMe F H H H F 50 0.11 454 MC 1145 S iso-prop H MeSMe F H H H F 2000.10 2,000 MC 1140 S H H MeSMe H H H H H >200 20 >10

What is claimed is:
 1. A compound of the formula:

wherein: X is —O, —CH₂, —CHK (wherein K is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl), —S, —NK (wherein K is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl), -aryl, -arylalkyl; R is —H, —C₁₋₄alkyl (containing one or more of heteroatoms like O, S, N), C₃₋₆cycloalkyl (containing one or more of heteroatoms like O, S, N), -aryl, arylalkyl, heterocycle; Y is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl; Z is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl; R₁ is —H, —C₁₋₄alkyl, halogen, —NO₂, —OW (wherein W is —H, —CH₃, -aryl), —SW (wherein W is —H, —CH₃, -aryl); R₂ is —H, —C₁₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃, -aryl), —SW (wherein W is —H, —CH₃, -aryl); R₃ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃, aryl), —SW (wherein W is —H, —CH₃, -aryl); R₄ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃, -aryl), —SW (wherein W is —H, —CH₃, -aryl); R₅ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃, -aryl), —SW (wherein W is —H, —CH₃, -aryl), or a pharmaceutically acceptable salt or soluble derivative thereof.
 2. A compound having formula A as claimed in claim 1 wherein X = O Y = H Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = O Y = H Z = H R = cPen R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F.


3. A compound having formula A as claimed in claim 1 wherein X = S Y = H Z = H R = sBu R₁ = NO₂ R₂ = H R₃ = H R₄ = H R₅ = H X = S Y = H Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = H X = S Y = H Z = H R = CH₃ R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = H R = ipr R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = H R = nBu R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = H R = iBu R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = H R = sBu R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = H R = cPen R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = H R = cEs R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = H R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = H R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = H R = nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = H R = iBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = H R = cPen R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = H R = cEs R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = CH₃ R = iPr R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = CH₃ R = cPen R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = CH₃ R = cEs R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = Et R = iPr R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = Et R = cPen R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = Et R = cEs R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = H Z = CH₃ R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = CH₃ R = iBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = CH₃ R = nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = CH₃ R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = CH₃ R = cPen R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = CH₃ R = cEs R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = Et R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = Et R = cPen R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = Et R = cEs R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = CH₃ R = cEs —CH═CH—CH═CH R₃ = H R₄ = H R₅ = H X = S Y = H Z = H R = sBu R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = H X = S Y = CH₃ Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = H X = S Y = CH₃ Z = H R = sBu R₁ = Cl R₂ = H R₃ = H R₄ = H R₅ = Cl X = S Y = CH₃ Z = H R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = H R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = H R = nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = H R = iBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = H R = cPen R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = H R = cEs R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = CH₃ R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = CH₃ R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = CH₃ R = cPe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = Et Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = iPr Z = H R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = CH₃ R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = CH₃ R = nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = CH₃ R = iBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = CH₃ R = cEs R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = H Z = H R = MeSMe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = CH₃ Z = H R = MeSMe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = Et Z = H R = MeSMe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = S Y = iPr Z = H R = MeSMe R₁ = F R₂ = H R₂ = H R₄ = H R₅ = F.


4. A compound having formula A as claimed in claim 1 wherein X = NH Y = H Z = H R = Et R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = nPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = cPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = MeOEt R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = cPe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = cEs R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = CH₃ R = cPe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = H R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = H R = cPe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = H R = benz R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = CH₃ R = cPe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = H R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = H R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = H R = nPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = H R = nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = CH₃ R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = CH₃ R = nPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = CH₃ R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = CH₃ R = nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = CH₃ R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = H Z = CH₃ R = cEs R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = CH₃ R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = CH₃ R = nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = NH Y = CH₃ Z = CH₃ R = cEs R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = H Z = H R = (CH₃)₂ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = H Z = H R = Me-Pip R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = H Z = H R = Morph R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = H Z = H R = S-morp R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = H Z = H R = Piper R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = H Z = H R = Pyrroli R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = H Z = H R = Et₂ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = H Z = H R = (nPr)₂ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = CH₃ Z = H R = (CH₃)₂ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = CH₃ Z = H R = Me-Pip R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = CH₃ Z = H R = Morph R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F X = N Y = CH₃ Z = H R = S-morp R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F.


5. A pharmaceutically acceptable salt or soluble derivative of a compound of claim
 1. 6. A process for the preparation of a compound having formula A as claimed in claim 1 wherein X═O, wherein the proper methyl arylacetylalkylacetate is reacted with O-methylisourea in presence of calcium hydroxide; the so obtained 2-O-methyl(5-alkyl)-6-benzyl(substituted)uracils are reacted with the proper potassium alkoxide according to scheme A.
 7. A process for the preparation of a compound having formula A as claimed in claim 1 wherein X═S, wherein the proper ethyl arylacetylalkylacetate is reacted with thiourea in presence of sodium methoxide; the so obtained 5-alkyl-6-benzyl(substituted)-2-thiouracils are reacted with methyl iodide or with an alkyl halide in a basic medium according to scheme B.
 8. A process for the preparation of the compounds having formula A as claimed in claim 1 wherein X═NK (wherein K is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl), wherein the proper S-methyl(5-alkyl)-6-benzyl(substituted)-2-thiouracil is reacted with the proper amine according to scheme C.
 9. A method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS, comprising administering to a mammal an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof.
 10. A pharmaceutical composition useful for inhibiting HIV reverse transcriptase, comprising an effective amount of a compound claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof, and a pharmaceutically acceptable carrier.
 11. A pharmaceutical composition useful for preventing or treating infection of HIV or for treating AIDS, comprising an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof, and a pharmaceutically acceptable carrier.
 12. A method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS, comprising administering to a mammal an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt or soluble derivative thereof in combination with another anti-HIV agent selected from the group consisting of abacavir, zidovudine, BILA 1906, BILA 2185, BM+51.0836: triazoloisoindolinone derivative, BMS 186,318: aminodiol derivative HIV-1 protease inhibitor, d4API, stavudine, efavirenz, HBY097, HEPT, KNI-272, L-697,593, L-735,524, L-697,661, L-FDDC, LFDOC, nevirapine, foscarnet, PMEA, PMPA, Ro 31-8959, RPI-3121, SC-52151, SC55389A, TIBO R82150, TIBO 82913, TSAO-m3T, U90152, UC: thiocarboxanilide derivatives, UC-781, UC-82, VB 11,328, amprenavir, XM 323, delaviridine, famciclovir, gancyclovir, penciclovir, indinavir, nelfinavir, ritonavir, saquinavir, DDI, DDC, Delaviridine, β-LddA, β-L-3′-azido-d5FC, carbovir, acyclovir, interferon, stavudine, (3′-azido-2′,3′-dideoxy-5-methyl-cytidine), 3′-azido nucleosides, β-D-dioxoiane nucleosides such as β-D-dioxolanylguanine (DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD), and β-D-dioxolanyl-6-chloropurine (ACP), D4T, FTC, 3TC, AZDU, and amprenavir. 